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氯胺酮、丙咪嗪以及两者联合用药对Wistar Kyoto大鼠抑郁样行为的作用

叶奎, 李倩倩, 金孝岠, 朋立超

皖南医学院附属弋矶山医院麻醉科，芜湖 241000；复旦大学附属上海市第五人民医院麻醉科，上海 200240

摘要

本文旨在研究氯胺酮、丙咪嗪或两者联合用药对Wistar Kyoto (WKY)大鼠抑郁样行为的治疗效果和机制。取6周龄Wistar大鼠作为正常对照，给同龄WKY大鼠(抑郁症模型)腹腔注氯胺酮(给药1周，停药1周)、丙咪嗪(给药2周)或氯胺酮联合丙咪嗪。行糖水偏好及强迫游泳实验观察各组大鼠抑郁样行为的变化，用Western blot检测大鼠缰核β钙/钙调素依赖蛋白激酶II (β form of calcium/calmodulin-dependent protein kinase type II, βCaMKII)和膜谷氨酸受体1 (glutamate receptor 1, GluR1)蛋白表达，以及前额叶皮质的膜GluR1蛋白表达。结果显示，与Wistar大鼠相比，WKY大鼠糖水偏好程度显著降低，强迫游泳实验中不动时间显著增加；单独氯胺酮治疗对WKY大鼠的抑郁样行为没有显著作用，而丙咪嗪或氯胺酮联合丙咪嗪治疗可显著减少WKY大鼠不动时间。与Wistar大鼠相比，WKY大鼠缰核βCaMKII和膜GluR1蛋白表达显著上调，前额叶皮质的膜GluR1蛋白表达显著下调；单独氯胺酮治疗对WKY大鼠缰核βCaMKII和膜GluR1蛋白表达没有显著作用，但可上调前额叶皮质的膜GluR1蛋白表达；丙咪嗪或氯胺酮联合丙咪嗪治疗均可显著下调WKY大鼠缰核βCaMKII和膜GluR1蛋白表达，上调前额叶皮质的膜GluR1蛋白表达，丙咪嗪对上述蛋白表达的作用和联合用药之间无显著差异。以上结果提示，丙咪嗪治疗2周显著改善了WKY大鼠的抑郁样行为，联合使用氯胺酮不能增强丙咪嗪的疗效；丙咪嗪的抗抑郁机制可能与缰核中βCaMKII及膜GluR1表达下调以及前额叶皮质的膜GluR1表达上调有关。

关键词： 氯胺酮; 丙咪嗪 ; 抗抑郁 ; β钙/钙调素依赖蛋白激酶II ; 谷氨酸受体1 ; 缰核 ; 前额叶皮质

分类号：R964

Effects of ketamine, imipramine, and their combination on depression-like behaviors in Wistar Kyoto rats

YE Kui, LI Qian-Qian, JIN Xiao-Ju, PENG Li-Chao

Department of Anesthesiology, Yijishan Hospital, Wannan Medical College, Wuhu 241000, China； Department of Anesthesiology, Fifth People's Hospital of Shanghai Affiliated to Fudan University, Shanghai 200240, China

Abstract

The aim of the present study was to investigate the effects of ketamine, imipramine, and ketamine plus imipramine on chronic depression-like behaviors of Wistar Kyoto (WKY) rats and underlying mechanism. Six-week-old Wistar rats were used as normal control. WKY rats, depression model animal, were injected intraperitoneally with ketamine (1 week, replaced with saline in 2nd week), imipramine (2 weeks), or ketamine in combination with imipramine. The depression-like behaviors were assessed by sucrose preference and forced swimming tests. Protein expressions of β form of calcium/calmodulin-dependent protein kinase type II (βCaMKII) and membrane fraction of glutamate receptor 1 (GluR1) were measured in corresponding brain tissue with Western blot. The results showed that, compared with Wistar rats, WKY rats exhibited decreased sucrose preference and extended immobility time. Ketamine alone did not affect depression-like behaviors of WKY, whereas imipramine or its combination with ketamine could significantly decrease the immobility time. Compared with Wistar rats, WKY rats showed up-regulated levels of βCaMKII and membrane GluR1 protein expressions in habenula, and down-regulated level of membrane GluR1 protein expressions in the prefrontal cortex. Imipramine or its combination with ketamine could reverse these changes of protein expressions in WKY rats. There was no difference in reversing effect between imipramine and its combination with ketamine. Ketamine alone did not affect the βCaMKII and membrane GluR1 protein expressions in the habenula, but increased membrane GluR1 protein expression in the prefrontal cortex of WKY rats. These results suggest 2-week imipramine treatment significantly improves depressive behavior in WKY rats; however, the addition of ketamine in the first week fails to enhance the effect of imipramine. The underlying mechanisms of imipramine’s anti-depressive effect may be associated with the down-regulation of βCaMKII and membrane GluR1 in the habenula, as well as the up-regulation of membrane GluR1 in the prefrontal cortex.

Key words: Ketamine; imipramine ; anti-depressant ; β form of calcium/calmodulin-dependent protein kinase type II ; glutamate receptor 1 ; habenula ; prefrontal cortex

收稿日期：2015-08-04　　录用日期：2015-12-02

通讯作者：朋立超　　E-mail: plichao@foxmail.com

引用本文：

叶奎, 李倩倩, 金孝岠, 朋立超. 氯胺酮、丙咪嗪以及两者联合用药对Wistar Kyoto大鼠抑郁样行为的作用[J]. 生理学报 2016; 68 (1): 12-18.

YE Kui, LI Qian-Qian, JIN Xiao-Ju, PENG Li-Chao. Effects of ketamine, imipramine, and their combination on depression-like behaviors in Wistar Kyoto rats. Acta Physiol Sin 2016; 68 (1): 12-18 (in Chinese with English abstract).